CIS is a potent checkpoint in NK cell-mediated tumor immunity

Rebecca B. Delconte, Tatiana B Kolesnik, Laura F. Dagley, Jai Rautela, Wei Shi, Eva M. Putz, Kimberley Stannard, Jian Guo Zhang, Charis En-Yi Teh, Matt Firth, Takashi Ushiki, Christopher E Andoniou, Mariapia A Degli-Esposti, Phillip P Sharp, Caroline E. Sanvitale, Giuseppe Infusini, Nicholas P.D. Liau, Edmond M Linossi, Christopher J Burns, Sebastian Carotta & 12 others Daniel H.D. Gray, Cyril Seillet, Dana S. Hutchinson, Gabrielle T Belz, Andrew I. Webb, Warren S. Alexander, Shawn S Li, Alex N Bullock, Jeffery J. Babon, Mark J. Smyth, Sandra E. Nicholson, Nicholas D Huntington

Research output: Contribution to journalArticleResearchpeer-review

71 Citations (Scopus)

Abstract

The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish -/- mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. Our data uncover a potent intracellular checkpoint in NK cell-mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function.

Original languageEnglish
Pages (from-to)816-824
Number of pages9
JournalNature Immunology
Volume17
Issue number7
DOIs
Publication statusPublished - 21 Jun 2016

Cite this

Delconte, R. B., Kolesnik, T. B., Dagley, L. F., Rautela, J., Shi, W., Putz, E. M., ... Huntington, N. D. (2016). CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nature Immunology, 17(7), 816-824. https://doi.org/10.1038/ni.3470
Delconte, Rebecca B. ; Kolesnik, Tatiana B ; Dagley, Laura F. ; Rautela, Jai ; Shi, Wei ; Putz, Eva M. ; Stannard, Kimberley ; Zhang, Jian Guo ; Teh, Charis En-Yi ; Firth, Matt ; Ushiki, Takashi ; Andoniou, Christopher E ; Degli-Esposti, Mariapia A ; Sharp, Phillip P ; Sanvitale, Caroline E. ; Infusini, Giuseppe ; Liau, Nicholas P.D. ; Linossi, Edmond M ; Burns, Christopher J ; Carotta, Sebastian ; Gray, Daniel H.D. ; Seillet, Cyril ; Hutchinson, Dana S. ; Belz, Gabrielle T ; Webb, Andrew I. ; Alexander, Warren S. ; Li, Shawn S ; Bullock, Alex N ; Babon, Jeffery J. ; Smyth, Mark J. ; Nicholson, Sandra E. ; Huntington, Nicholas D. / CIS is a potent checkpoint in NK cell-mediated tumor immunity. In: Nature Immunology. 2016 ; Vol. 17, No. 7. pp. 816-824.
@article{88d43f40fc3947e8aa2aa1b3473af391,
title = "CIS is a potent checkpoint in NK cell-mediated tumor immunity",
abstract = "The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish -/- mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. Our data uncover a potent intracellular checkpoint in NK cell-mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function.",
author = "Delconte, {Rebecca B.} and Kolesnik, {Tatiana B} and Dagley, {Laura F.} and Jai Rautela and Wei Shi and Putz, {Eva M.} and Kimberley Stannard and Zhang, {Jian Guo} and Teh, {Charis En-Yi} and Matt Firth and Takashi Ushiki and Andoniou, {Christopher E} and Degli-Esposti, {Mariapia A} and Sharp, {Phillip P} and Sanvitale, {Caroline E.} and Giuseppe Infusini and Liau, {Nicholas P.D.} and Linossi, {Edmond M} and Burns, {Christopher J} and Sebastian Carotta and Gray, {Daniel H.D.} and Cyril Seillet and Hutchinson, {Dana S.} and Belz, {Gabrielle T} and Webb, {Andrew I.} and Alexander, {Warren S.} and Li, {Shawn S} and Bullock, {Alex N} and Babon, {Jeffery J.} and Smyth, {Mark J.} and Nicholson, {Sandra E.} and Huntington, {Nicholas D}",
year = "2016",
month = "6",
day = "21",
doi = "10.1038/ni.3470",
language = "English",
volume = "17",
pages = "816--824",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "7",

}

Delconte, RB, Kolesnik, TB, Dagley, LF, Rautela, J, Shi, W, Putz, EM, Stannard, K, Zhang, JG, Teh, CE-Y, Firth, M, Ushiki, T, Andoniou, CE, Degli-Esposti, MA, Sharp, PP, Sanvitale, CE, Infusini, G, Liau, NPD, Linossi, EM, Burns, CJ, Carotta, S, Gray, DHD, Seillet, C, Hutchinson, DS, Belz, GT, Webb, AI, Alexander, WS, Li, SS, Bullock, AN, Babon, JJ, Smyth, MJ, Nicholson, SE & Huntington, ND 2016, 'CIS is a potent checkpoint in NK cell-mediated tumor immunity', Nature Immunology, vol. 17, no. 7, pp. 816-824. https://doi.org/10.1038/ni.3470

CIS is a potent checkpoint in NK cell-mediated tumor immunity. / Delconte, Rebecca B.; Kolesnik, Tatiana B; Dagley, Laura F.; Rautela, Jai; Shi, Wei; Putz, Eva M.; Stannard, Kimberley; Zhang, Jian Guo; Teh, Charis En-Yi; Firth, Matt; Ushiki, Takashi; Andoniou, Christopher E; Degli-Esposti, Mariapia A; Sharp, Phillip P; Sanvitale, Caroline E.; Infusini, Giuseppe; Liau, Nicholas P.D.; Linossi, Edmond M; Burns, Christopher J; Carotta, Sebastian; Gray, Daniel H.D.; Seillet, Cyril; Hutchinson, Dana S.; Belz, Gabrielle T; Webb, Andrew I.; Alexander, Warren S.; Li, Shawn S; Bullock, Alex N; Babon, Jeffery J.; Smyth, Mark J.; Nicholson, Sandra E.; Huntington, Nicholas D.

In: Nature Immunology, Vol. 17, No. 7, 21.06.2016, p. 816-824.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - CIS is a potent checkpoint in NK cell-mediated tumor immunity

AU - Delconte, Rebecca B.

AU - Kolesnik, Tatiana B

AU - Dagley, Laura F.

AU - Rautela, Jai

AU - Shi, Wei

AU - Putz, Eva M.

AU - Stannard, Kimberley

AU - Zhang, Jian Guo

AU - Teh, Charis En-Yi

AU - Firth, Matt

AU - Ushiki, Takashi

AU - Andoniou, Christopher E

AU - Degli-Esposti, Mariapia A

AU - Sharp, Phillip P

AU - Sanvitale, Caroline E.

AU - Infusini, Giuseppe

AU - Liau, Nicholas P.D.

AU - Linossi, Edmond M

AU - Burns, Christopher J

AU - Carotta, Sebastian

AU - Gray, Daniel H.D.

AU - Seillet, Cyril

AU - Hutchinson, Dana S.

AU - Belz, Gabrielle T

AU - Webb, Andrew I.

AU - Alexander, Warren S.

AU - Li, Shawn S

AU - Bullock, Alex N

AU - Babon, Jeffery J.

AU - Smyth, Mark J.

AU - Nicholson, Sandra E.

AU - Huntington, Nicholas D

PY - 2016/6/21

Y1 - 2016/6/21

N2 - The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish -/- mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. Our data uncover a potent intracellular checkpoint in NK cell-mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function.

AB - The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish -/- mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. Our data uncover a potent intracellular checkpoint in NK cell-mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function.

UR - http://www.scopus.com/inward/record.url?scp=84969760211&partnerID=8YFLogxK

U2 - 10.1038/ni.3470

DO - 10.1038/ni.3470

M3 - Article

VL - 17

SP - 816

EP - 824

JO - Nature Immunology

JF - Nature Immunology

SN - 1529-2908

IS - 7

ER -

Delconte RB, Kolesnik TB, Dagley LF, Rautela J, Shi W, Putz EM et al. CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nature Immunology. 2016 Jun 21;17(7):816-824. https://doi.org/10.1038/ni.3470